Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China.
Jiangxi Provincial Key Laboratory of Hematology, Nanchang, Jiangxi, China.
Mol Cancer Res. 2024 Feb 1;22(2):125-136. doi: 10.1158/1541-7786.MCR-23-0282.
Exosomal long noncoding RNAs (lncRNA) derived from cancer cells are implicated in various processes, including cancer cell proliferation, metastasis, and immunomodulation. We investigated the role and underlying mechanism of exosome-transmitted lncRNA NEAT1 in the immune escape of multiple myeloma cells from natural killer (NK) cells. Multiple myeloma cells and samples from patients with multiple myeloma were obtained. The effects of multiple myeloma cell-derived exosomes (multiple myeloma exosomes) and exosomal NEAT1 on the functions of NK cells were evaluated using EdU staining, CCK-8, flow cytometry, and ELISA. Chromatin and RNA immunoprecipitation were performed to identify interactions between NEAT1, enhancer of Zeste Homolog 2 (EZH2), and pre-B-cell leukemia transcription factor 1 (PBX1). A xenograft tumor model was constructed to verify the effects of exosomal NEAT1 on tumor growth. qRT-PCR, Western blot analysis, and IHC were conducted to detect related genes. NEAT1 levels were upregulated in multiple myeloma tumor tissues, multiple myeloma cells, and multiple myeloma exosomes. Multiple myeloma exosomes suppressed cell proliferation, promoted apoptosis, reduced natural killer group 2, member D (NKG2D)-positive cells, and the production of TNFα) and interferon-gamma (IFN-γ) in NK cells, whereas NEAT1-silenced exosomes had little effect. NEAT1 silenced PBX1 by recruiting EZH2. PBX1 knockdown abrogated the effects of NEAT1-silenced exosomes on NK and multiple myeloma cells. NEAT1-silenced exosomes inhibited tumor growth in mice, decreased Ki67 and PD-L1, and increased NKG2D, TNFα, and IFNγ in tumor tissues. In summary, multiple myeloma cell-derived exosomal NEAT1 suppressed NK-cell activity by downregulating PBX1, promoting multiple myeloma cell immune escape. This study suggests a potential strategy for treating multiple myeloma.
This study reveals that exosomal NEAT1 regulates EZH2/PBX1 axis to inhibit NK-cell activity, thereby promoting multiple myeloma cell immune escape, which offers a novel therapeutic potential for multiple myeloma.
来自癌细胞的外泌体长非编码 RNA（lncRNA）被认为参与了多种过程，包括癌细胞的增殖、转移和免疫调节。我们研究了外泌体传递的 lncRNA NEAT1 在多发性骨髓瘤细胞逃避自然杀伤（NK）细胞免疫中的作用和潜在机制。获得多发性骨髓瘤细胞和多发性骨髓瘤患者的样本。通过 EdU 染色、CCK-8、流式细胞术和 ELISA 评估多发性骨髓瘤细胞衍生的外泌体（多发性骨髓瘤外泌体）和外泌体 NEAT1 对 NK 细胞功能的影响。进行染色质和 RNA 免疫沉淀以鉴定 NEAT1、EZH2 同源物 2（EZH2）和前 B 细胞白血病转录因子 1（PBX1）之间的相互作用。构建异种移植肿瘤模型以验证外泌体 NEAT1 对肿瘤生长的影响。进行 qRT-PCR、Western blot 分析和 IHC 以检测相关基因。NEAT1 水平在多发性骨髓瘤肿瘤组织、多发性骨髓瘤细胞和多发性骨髓瘤外泌体中上调。多发性骨髓瘤外泌体抑制细胞增殖，促进细胞凋亡，减少 NK 细胞中自然杀伤组 2，成员 D（NKG2D）阳性细胞和 TNFα）和干扰素-γ（IFN-γ）的产生，而沉默 NEAT1 的外泌体影响不大。NEAT1 通过募集 EZH2 沉默 PBX1。PBX1 敲低消除了沉默 NEAT1 的外泌体对 NK 和多发性骨髓瘤细胞的影响。沉默 NEAT1 的外泌体抑制小鼠肿瘤生长，降低 Ki67 和 PD-L1，并增加肿瘤组织中的 NKG2D、TNFα 和 IFNγ。总之，多发性骨髓瘤细胞来源的外泌体 NEAT1 通过下调 PBX1 抑制 NK 细胞活性，从而促进多发性骨髓瘤细胞的免疫逃逸。这项研究为多发性骨髓瘤的治疗提供了一种新的潜在策略。
这项研究表明，外泌体 NEAT1 通过调节 EZH2/PBX1 轴抑制 NK 细胞活性，从而促进多发性骨髓瘤细胞的免疫逃逸，为多发性骨髓瘤提供了一种新的治疗潜力。
